The invention relates to a soft gelatin capsule comprising S-adenosylmethionine (SAMe) and a method for producing such a capsule.
S-adenosylmethionine participates in a great number of metabolic processes of fundamental importance for human organism, and consequently its deficiency lies at the basis of many organic malfunctions.
S-adenosylmethionine is a natural molecule synthesized from the amino acid methionine in the presence of magnesium and adenosine triphosphate (ATP). The SAMe molecule is a carrier of methyl groups and provides a sulfur molecule as well. The liver is a site of methylation and sulfation reactions necessary for detoxification, and can use SAMe to assist in these processes. SAMe is also a cofactor in several metabolic reactions. By donating its methyl group, SAMe is converted to adenosylhomocysteine which, in turn, is rapidly hydrolysed to adenosine and homocysteine and eventually to the amino acid, cysteine.
S-adenosylmethionine is necessary for the production of Glutathione, the primary antioxidant found in the liver. SAMe has also been found effective in the treatment of Cholestasis. SAMe is also used in the treatment of fibromyalgia, osteoarthritis and depression.
SAMe is a highly temperature sensitive and moisture sensitive material. Therefore, several workers have attempted to provide stable salts of SAMe which can be used in drug formulations (e.g. U.S. Pat. Nos. 5,114,931 and 4,309,177 which are incorporated herein by reference). Two basic classes of derivatives have emerged, such as 1-4 butane sulphonates and disulphate tosylates. Examples of such salts can be found in U.S. Pat. No. 3,893,999 (SAMe tripara toulene sulphonate) and U.S. Pat. No. 4,057,686. These salts can be prepared by conventional methods such as fermentation or the synthetic route. These salts also need to be stored generally at 8 to 15xc2x0 C. in a cool dry place.
The salts of U.S. Pat. No. 3,893,999 are said to be sufficiently stable at 25xc2x0 C. and U.S. Pat. Nos. 3,954,726 and 4,057,686 provide SAMe salts claimed to be stable at 45xc2x0 C. Thus, most SAMe salts are hygroscopic and quickly degrade on exposure to moisture and heat. Pharmacokinetic studies conducted in respect of SAMe suggest that the drug is mainly absorbed in the intestinal tract, specifically, the duodenum. Currently, SAMe is available in the market in the tablet form. The absorption time of this drug in solid dosage form is relatively long and erratic for at least two reasons: onexe2x80x94the drug is introduced into the body as a solid: it therefore must dissolve before it can be absorbed by the body; second reason is the acidic environment of the stomach. SAMe salts are influenced by the highly acidic environment of the stomach and often, the active ingredient does not get absorbed in the intestine as intended or desired by the manufacturer.
There is thus, a pronounced need in the art to provide a physically stable and durable dosage form that will promote timely absorption of the drug.
The prior art is replete with examples of drugs wherein one particular dosage form has been found unsuitable and alternative forms have been provided. Therefore, it would be ideal to provide an alternative dosage form of SAMe, which can be easily absorbed by the human body.
Extended release delivery systems capable of releasing a drug after a predetermined time at target site have been studied to address the problematic areas in sustained release preparations. It is found that encapsulation of the medicinal agent may be a good option, considering consumer acceptability, reduced scope for tampering and capacity to release the drug after a predetermined lag time. This art of encapsulation has gained importance over the years as an alternative to tablets. The capsule form also presents several significant advantages over tablets, like they are tasteless, odorless, easy to swallow, etc.
As said earlier, SAMe being hygroscopic, is susceptible to degradation on exposure to heat and moisture. It is, however, more stable in a lipophilic environment. It should theoretically be possible to formulate and provide SAMe in an encapsulated form for good bioavailability, using methods known in the art.
Several patents providing various xe2x80x98stablexe2x80x99 salts of SAMe, such as U.S. Pat. Nos. 4,109,079; 4,242,505; 4,764,603; 5,073,546; 5,128,249; 5,238,741 and 6,093,703, make references and even suggest the preparation of pharmaceutical formulations using these salts as active ingredients. U.S. Pat. No. 5,128,249 provides sulpho salts suitable for oral use and describes in Example 13, the ingredients of a specific dosage formxe2x80x94the capsule.
The Applicant has found that several practical problems are encountered when encapsulation of SAMe or its derivatives is attempted. Encapsulation of SAMe is not as easy as theoretised. The first problem of course is the hygroscopic nature and low pH of SAMe, which does not permit easy encapsulation since the initial high water content of the gelatin shell has an adverse effect on the compound. The second problem is that if the tablet is enteric coated, the coating has to be optimized for the desired availability of SAMe at the target site i.e anterior part of the intestine.
It is on account of these problems that the encapsulated dosage form of SAMe salts are not available in the market. The prior art does not identify these problems nor suggest any solutions to overcome the same. Beyond the development of a simulated capsule like medicament, several factors and considerations must be met to commercially produce a capsule which is storage stable and acceptable to the consumers.
To overcome and provide a solution to the problems in the prior art, the Applicant has conducted a detailed investigation and has developed a pharmaceutical formulation containing SAMe as the active ingredient suitable for encapsulation and a method for producing the said soft gelatin capsules.
In fact, people in the art have not envisaged coating SAMe with soft gelatin film for the reason that because such encapsulation would cause deterioration of SAMe. However, as opposed to that, the Applicant tried the encapsulation and to their surprise found that such encapsulation really achieved the advantages of enhancing the shelf life of SAMe and at the same time achieving 95% protection from degradation.
The main object of the invention is to provide a soft gelatin capsule encapsulating SAMe as the active ingredient.
Another object is to provide a method for the encapsulation of SAMe.
Yet another object is to provide a method for producing the soft gelatin capsules of the invention.
In accordance with the above and other objectives, the invention provides a soft gelatin capsule containing S-adenosylmethionine or its stable salts as active ingredients.